Szlaga, A. | Search bioRxiv

bioRxiv2024

Mu-opioid receptor activation potentiates excitatory transmission at the habenulo-peduncular synapse

The continuing opioid epidemic poses a huge burden on public health. Identifying the neurocircuitry involved and how opioids modulate their signaling is essential for developing new therapeutic strategies. The medial habenula (MHb) is a small epithalamic structure that projects predominantly to the interpeduncular nucleus (IPN) and represents a mu-opioid receptor (MOR) hotspot. This habenulo-peduncular (HP) circuit can regulate nicotine and opioid withdrawal; however, little is known about the physiological impact of MOR on its function. Using MOR-reporter mice, we observed that MORs are expressed in a subset of MHb and IPN cells. Patch-clamp recordings revealed that MOR activation inhibited action potential firing in MOR+ MHb neurons and induced an inhibitory outward current in IPN neurons, consistent with canonical inhibitory effects of MOR. We next used optogenetics to stimulate MOR+ MHb axons to investigate the effects of MOR activation on excitatory transmission at the HP synapse. In contrast to its inhibitory effects elsewhere, MOR activation significantly potentiated evoked glutamatergic transmission to IPN. The facilitatory effects of MOR activation on glutamate co-release was also observed from cholinergic-defined HP synapses. The potentiation of excitatory transmission mediated by MOR activation persisted in the presence of blockers of GABA receptors or voltage-gated sodium channels, suggesting a monosynaptic mechanism. Finally, disruption of MOR in the MHb abolished the faciliatory action of DAMGO, indicating that this non-canonical effect of MOR activation on excitatory neurotransmission at the HP synapse is dependent on pre-synaptic MOR expression. Our study demonstrates canonical inhibitory effects of MOR activation in somatodendritic compartments, but non-canonical faciliatory effects on evoked glutamate transmission at the HP synapse, establishing a new mode by which MOR can modulate neuronal function.

neuroscience↗

bioRxiv2023

Mitochondrial fitness influences neuronal excitability of dopaminergic neurons from patients with idiopathic form of Parkinson's disease

Parkinson disease is the second most common neurodegenerative disease defined by presence of Lewy bodies and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). There are three types of PD - familial, early-onset and idiopathic. Idiopathic PD (IPD) accounts for approximately 90% of all PD cases. Mitochondrial dysfunction accompanies the pathogenesis of Parkinsons disease. Loss of mitochondrial function increases oxidative stress and calcium buffering, which in turn hinders the production of ATP and disrupts the functioning of dopaminergic neurons. The main barrier in PD research was the lack of proper human models to study the mechanisms of PD development and progression. Using induced pluripotent stem (iPS) cells we generated patient-specific dopaminergic neurons. We observed differences in the mitochondria fitness but not differences in mitochondria mass, morphology or membrane potential. Expression of OXPHOS mitochondrial complexes were lower in PD patients in comparison to control group what resulted in changes in mitochondria respiratory status. We observed also lower expression levels of Na+/K+-ATPase subunits and ATP-sensitive K+ (K-ATP) channel subunits. The lower oxygen consumption rate and extracellular acidification rate values were observed in dopaminergic progenitors and iPSC from PD patients compared to the control group. Importantly, observed decrease in the availability of ATP and in the energy consumption, as well as changes in acidification, may constitute contributing factors to the observed reduced neuronal excitability of PD patients dopaminergic neurons.

neuroscience↗